Yet, you would be hard pressed to find much coverage of this vaccine -- or, for that matter, any experimental cancer vaccine -- emanating from this year's ASCO meeting. Does this mean that the early results haven't held up? Or that researchers have determined that the vaccine concept -- teaching the immune system to recognize and then destroy rogue cancer cells -- is flawed? Au contraire: Data on a number of experimental cancer vaccines were reported at ASCO this year -- including Therion Biologics Corp.'s PROSTVAC prostate cancer vaccines, Vical Inc.'s Allovectin-7 vaccine for metastatic melanoma and Cell Genesys' vaccines for lung cancer and prostate cancer. And, though the results didn't grab any headlines, they do provide further evidence that supports the use of vaccines to fight cancer -- or at least to stop its fearful spread.


For instance, all prostate cancer patients who received Therion Biologics' pox virus vaccines in a Phase II clinical trial demonstrated stabilized levels of prostate-specific antigen (PSA, whose circulating levels serve as a marker of disease progression) and reduced clinical progression of their disease. Clinical investigators tested three different vaccination regimens in 70 patients, all of whom had undergone surgery or radiation treatment to remove primary prostate tumors. One group received four doses of fowlpox-PROSTVAC (in which a recombinant fowlpox virus was engineered to express human PSA, thus stimulating an immune response against the tumor cells); the second group received three doses of vaccinia-PROSTVAC (which employs a PSA-expressing recombinant vaccinia virus) followed by one dose of fowlpox-PROSTVAC; and the third received one dose of vaccinia-PROSTVAC followed by three doses of fowlpox-PROSTVAC (the prime-boost regimen). All regimens worked at delaying time to PSA progression, but the prime-boost approach is most promising. In this group, 62 percent of the patients were PSA progression free at 24 months post-treatment. In addition, 78 percent of all patients enrolled in the trial remained free of tumor metastases.

And Vical updated the survival data from its Phase II registration trial of Allovectin-7, a vaccine for metastatic melanoma that consists of a DNA/ lipid complex containing the human gene for HLA-B7 (a histocompatibility antigen that stimulates the immune system) that is injected directly into the tumor. The cancer cells take up the product and then express the HLA-B7 surface marker. It's thought that this process alerts the patient's immune system to seek out the tumor cells -- which are now marked as being "non-self" -- and set about destroying them.

At last year's ASCO meeting, Vical reported interim data for 73 patients who received at least one injection of the experimental vaccine (intent-to-treat patient population), including 54 patients who got at least one full treatment cycle (evaluable patients). All patients had failed other treatments before enrolling in this trial. The therapy resulted in systemic clinical responses in about 11 percent of patients (short of the defined endpoint of 15 percent clinical response rate), with a median duration of response of five months (better than the defined endpoint of four months). Additionally, about 19 percent of the patients had achieved stable disease. A year later, the estimated median survival for all patients treated in the trial (a total of 78) was 14.3 months. Moreover, nearly 90 percent of the initial responders were still alive.


These results are not sufficient by themselves to support a regulatory submission, according to the company. But Vical has also conducted a Phase III registration trial of Allovectin-7, this time in combination with chemotherapy in chemotherapy-naïve patients. That trial -- in which one of the primary endpoints is improvement in the time to disease progression -- is now complete and the data are being collected and analyzed.

If the trial data confirm the primary endpoint, they will add more credence to the premise that cancer can be treated as a chronic disease, with vaccines keeping it in check. This is an important point: About four years ago, it became clear to cancer researchers that biologics can be combined with chemotherapy (in doses that are not noxious) for treating cancer, and that the outcome improves the patient's quality of life. For many types of tumors, this approach might actually mean that doctors can prolong the time to recurrence of a tumor for the life of the patient.


Based on what she learned at the ASCO meeting, Gail Maderis, president of Genzyme Molecular Oncology, said that investigators are making "good, steady progress" on the cancer vaccine front, which is "coming into its own." However, she explained, "everyone is facing challenges." The standard clinical protocols for treating cancer are designed to test drugs; vaccines, on the other hand, have a different mode of action and thus "the assays [used to demonstrate efficacy] and the clinical endpoints need to change," she explained. "We're essentially creating a new [treatment] paradigm."

Determining the endpoints presents a dilemma, because "what we use in a trial that helps us determine early on which approaches merit more work might be separate to some extent from what the FDA will need," she continued. "It's clear that the FDA will look for survival as an endpoint with these new drugs." However, she added, "there are certain indications (such as pain management in prostate cancer) where palliation of disease may be approvable as an endpoint. The agency may also allow time to progression of disease as an endpoint, but beyond that it will come back to survival."

On the other hand, although it's not clear whether reduction of tumor mass will impact survival, this measurement is useful in early studies, Maderis said. "These studies will take too long if we have to wait for survival."

Genzyme Molecular Oncology, which is also developing cancer vaccines, uses response rate (50 percent shrinkage of tumor mass), stable disease, and immunologic endpoints in its early-stage trials. For instance, "we take a blood sample to see if it contains T cells that recognize the tumor. That gives us an indication that we have stimulated the immune system," Maderis said. It doesn't, however, prove that the vaccine will elicit a clinical response (i.e., tumor regression).

Part of the challenge for cancer vaccines comes from the fact that many patients enrolled in these trials have been "heavily pre-treated with chemotherapy or radiation, which tend to damage the immune system." Thus, "we are starting from a low baseline level of immunity and trying to increase the number of immune cells so they can overcome a rapidly growing cancer." This might take a while: "It's common to see a clinical response several months after the initiation of the vaccination schedule," Maderis explained. "In patients with late-stage disease, it might be too little, too late."


Genzyme Molecular Oncology is developing two types of cancer vaccines, both of which use the patient's dendritic cells, specialized immune system cells found in the skin (where large populations reside), lymph nodes and elsewhere, that present antigens to T cells. In cases where specific tumor antigens are not known, the company fuses the patient's own (inactivated) tumor cells with the dendritic cells. The company has already conducted Phase I/II trials of patient-specific fusion vaccines in breast cancer, melanoma and kidney cancer.

In cases where specific tumor antigens are known, Genzyme Molecular Oncology either transfects the patient's dendritic cells with adenoviral vectors encoding those genes ex vivo and then injects the patient, or it administers the vectors directly via intradermal injection.

Among other cancers under investigation, the company's testing its antigen-specific vaccines (encoding the Melan-A/MART-1 and gp100 antigens) in two Phase I/II melanoma trials. The first, which used the ex vivo approach, is now complete; it was conducted in late-stage patients with bulky disease, Maderis said, where it's possible to measure the reduction in tumor mass. Preliminary data presented in December 2001 demonstrated that immunologic or clinical responses occurred in 14 of 20 patients enrolled in the trial. One patient had a complete clinical response, one had a partial response and a third demonstrated stable disease.

The second trial, which uses in vivo vaccination and is still enrolling patients, is testing the vaccine in patients with earlier stage disease whose tumors have been surgically removed. These patients enter the trial with no evidence of disease, Maderis said. In this trial, the company will compare several different dosing regimens to ascertain the optimum vaccination schedule, she added, and will monitor the patients' immune responses over time.


Cell Genesys has also developed ex vivo and in vivo cancer vaccines, but it's taken a different approach.

In the Phase I/II lung cancer trial reported at ASCO 2001, the company tested its patient-specific GVAX product, which is made by genetically modifying the patient's own tumor cells ex vivo with the gene for GM-CSF (an immune stimulator), lethally irradiating the cells, and then injecting them back into the patient.

That trial is now complete. In the end, of the 26 advanced-stage patients (all of whom had failed prior therapy), three achieved a complete response (tumors had disappeared at all disease sites) with a median duration of at least 11 months and seven had stable disease with a median duration of at least six months. In the same trial, Cell Genesys also tested 10 patients with early stage disease at high risk of recurrence following surgery. Of the 10, eight were disease-free with a median duration of at least 12 months. In addition, this vaccine was also shown to induce a cellular immune response to the cancer and the formation of new anti-cancer antibodies in the blood. These results were encouraging enough that Cell Genesys is planning on initiating Phase III trials late this year, probably in the fourth quarter, according to chairman and CEO Stephen Sherwin.

The company uses adenoviral vectors to transfect patient-specific tumor cells. Because these vectors don't require dividing cells to do their work (as opposed to retroviral vectors), the vaccine now can be produced in a matter of hours rather than days or weeks. "It's a fast, efficient process, which can be scaled up for Phase III trials and commercial use," Sherwin said.

Meanwhile, the Foster City, CA company has begun testing a new formulation of its patient-specific vaccine -- one in which the patient's own irradiated tumor cells are mixed with a non patient-specific GVAX cell line product that secretes GM-CSF. Interim data from a Phase I/II lung cancer trial on this new formulation reported at the recent ASCO meeting demonstrated evidence of anti-tumor immunity. The new product format, if it proves out, will be even easier to manufacture and commercialize, for the non-patient specific portion can be waiting on the shelf and mixed with a patient's cells just prior to vaccination.

Cell Genesys has vaccines in development for numerous other cancers, as well -- and some of them are non patient-specific. Its prostate cancer vaccine, for instance, consists of two separate prostate cancer cell lines (which express different antigens), genetically modified to secrete GM-CSF and then irradiated before being injected into the patient. At this year's ASCO meeting, clinicians reported long-term survival data from a Phase II trial in patients with hormone refractory prostate cancer metastatic to bone.

In the 34-patient study, seven of 10 patients (70 percent) receiving the higher of two doses of the vaccine are alive 2.5 years after treatment (median survival greater than 30 months). Of the 24 patients who received the lower dose, two were lost to follow-up, but nine of the others (41 percent) are also alive 2.5 years after treatment (median survival 22 months). At either dose, the survival rates are impressive: The reported median survival rate for patients receiving chemotherapy, the standard of care, is seven to 11 months. According to Sherwin, there is only one FDA-approved drug for treating these patients -- Immunex Corp.'s Novantrone -- which, although it can reduce the amount of bone pain, "doesn't have any measurable impact on survival."

Not surprisingly, Cell Genesys is gearing up to start Phase III trials of its prostate cancer vaccine in the first half of 2003.

Still, it's important to note that immune-based therapy works well in some patients but not in others. The exact reasons are unclear, but can be explained, at least in part, by "the genetics of the immune response," Sherwin said. For instance, in a GVAX pancreatic cancer trial, three of eight treated patients were alive and cancer-free four years after therapy. The other five patients "died much earlier." The only patients who had a positive skin test to the vaccine (i.e., immune response) were the three survivors, he continued.

"There is no doubt in my mind that if we are able to stimulate an immune response appropriately, we can have this kind of benefit. It fits with what we think about disease. Immune surveillance systems normally get rid of cancer cells," Sherwin said. But, in cancer, those surveillance systems fail. "If we figure out how to reverse immune suppression, we can get back in control."